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JAC Advance Access originally published online on March 22, 2009
Journal of Antimicrobial Chemotherapy 2009 63(6):1215-1222; doi:10.1093/jac/dkp097
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Influence of different resistance traits on the competitive growth of Haemophilus influenzae in antibiotic-free medium and selection of resistant populations by different β-lactams: an in vitro pharmacodynamic approach

Natalia González1, Lorenzo Aguilar1,*, Luis Alou1, Maria-Jose Giménez1, David Sevillano1, Martha Torrico1, Fabio Cafini1, Pilar Coronel2 and Jose Prieto1

1 Microbiology Department, School of Medicine, Univ. Complutense, Avda. Complutense s/n, 28040 Madrid, Spain 2 Scientific Department, Tedec-Meiji Farma S.A., Ctra. M-300, Km. 30,500, 28802 Alcalá de Henares, Madrid, Spain

Received 4 December 2008; returned 6 February 2009; revised 12 February 2009; accepted 26 February 2009

* Corresponding author. Tel: +34-91-3941505; Fax: +34-91-3941511; E-mail: laguilar{at}med.ucm.es

Objectives: The aim was to study the pharmacodynamics of cefditoren, amoxicillin/clavulanic acid and cefuroxime against mixed Haemophilus influenzae strains.

Methods: Isolates [MICs (mg/L) of cefditoren, cefuroxime and amoxicillin/clavulanic acid] used were: one β-lactamase-negative (β–; 0.015, 1 and 1), one β-lactamase-positive (β+; 0.03, 4 and 8) and two strains exhibiting ftsI gene mutations [one β– ampicillin-resistant (BLNAR; 0.015, 8 and 4) and one β+ amoxicillin/clavulanic acid-resistant (BLPACR; 0.03, 8 and 4)]. A computerized pharmacodynamic model simulating free antibiotic concentrations (calculated considering reported percentages of protein binding) of 400 mg twice-daily cefditoren, 500 mg twice-daily cefuroxime and 875/125 mg three times daily amoxicillin/clavulanic acid was used to explore antibacterial activity against initial mixed inocula with 25% of each strain. Areas under bacterial curves (AUBCs) from 0 to 24 h (log cfu·h/mL) were calculated and differences between values in antibiotic-free (AUBCK) and in antibiotic simulations determined (ABBC0–24 = AUBCK0–24–AUBC0–24).

Results: In antibiotic-free medium, total population increased by 1.7 log10 cfu/mL from 0 to 24 h: final composition {approx}90% β–, {approx}6.5% β+, {approx}2.5% BLNAR and {approx}1% BLPACR. At the end of antibiotic simulations, the predominant population was BLPACR followed by β+ after amoxicillin/clavulanic acid or BLNAR after cefuroxime exposures. ABBC0–24 was higher (P < 0.01) for cefditoren compared with cefuroxime or amoxicillin/clavulanic acid whether considering total population (70.4 versus {approx}33), β+ (77.8 versus {approx}52), BLNAR (66.1 versus 18.6–30.4) or BLPACR (40.8 versus {approx}0).

Conclusions: Cefditoren offered higher antibacterial effect than cefuroxime and amoxicillin/clavulanic acid against a mixed population of H. influenzae strains due to its higher activity against β-lactamase-producing strains and those carrying ftsI gene mutations.

Keywords: amoxicillin/clavulanic acid , in vitro simulation , cefditoren


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